Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-03-22
2003-01-21
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C514S454000
Reexamination Certificate
active
06509005
ABSTRACT:
DESCRIPTION
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is generally related to the therapeutic use of &Dgr;
9
Tetrahydrocannabinol (&Dgr;
9
THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of &Dgr;
9
THC to patients suffering from nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, epilepsy, glaucoma, bronchial asthma, mood disorders, and the like.
2. Background Description
“Medical Marijuana” is a timely and controversial subject that is currently receiving widespread public attention. While marijuana is usually thought of as an illegal “recreational” drug, it also has a long history as a medicine. In 1997, the National Institutes of Health (NIH) released a review of the scientific data concerning potential therapeutic uses for marijuana. In that review, the NIH found that marijuana may indeed have beneficial medicinal effects and recommended that researchers develop alternative dosage forms for the drug, such as a “smoke free” inhaled delivery system (1). Table 1 summarizes the findings of several studies (references 2-18) that have documented therapeutically beneficial medicinal uses of the major active component of marijuana, &Dgr;
9
tetrahydrocannabinol (&Dgr;
9
THC).
TABLE 1
The Use of &Dgr;
9
THC for the Treatment of Assorted Clinical Conditions
Condition
and Number
Administration
of Patients
Route and Dose
Findings
Reference
AIDS-associated
Oral placebo,
Long term THC
Beal et al.,
anorexia and
2.5 mg THC once
treatment was
1997
cachexia; 94
or twice daily
well tolerated;
patients; 12
increasing to 20
THC improved
months
mg daily
appetite and
only tended to
increase weight
compared to
controls
AIDS-associated
Oral placebo or
57% and 69%
Beal et al.,
anorexia and
2.5 mg THC
of vehicle and
1995
cachexia; 139
twice daily
THC patients
patients; 42 days
were evaluable
for efficacy.
Appetite
increased 38%
over baseline
for THC group
compared to only
8% for the
placebo group.
THC also
decreased nausea.
No significant
changes were
found between
the groups for
weight change.
Nausea and
Oral THC, 15
Reduction in
McCabe et al.,
emesis due to
mg/m
2
chemotherapy-
1988
cancer
induced nausea
chemotherapy; 36
and vomiting in
patients who
64% of patients
had experienced
given THC
severe nausea
compared to
and vomiting
prochloperazine;
that was
side effects
refractory to
included
prochlorperazine
dysphoria;
or
authors
thiethylperazine
recommend
initial THC
dose of 5
mg/m
2
Nausea and
Oral 5 or
72% of patients
Lucas and
emesis due to
15 mg/m
2
THC
exhibited a THC-
Laszlo, 1980
cancer
four times per day
induced partial
chemotherapy; 53
or complete
patients which
blockade of
were refractory
vomiting
to other
antiemetics
Nausea and
Oral 10 mg/m
2
THC more
Sallan et al.,
emesis due to
THC of
effective than
1980
cancer
prochloperazine
prochloperazine
chemotherapy; 84
patients
Nausea and
Oral 15 mg THC,
Equal antiemetic
Frytak et al.,
emesis due to
10 mg
effects between
1979
cancer
prochloperzine
THC and
chemotherapy;
or placebo
prochlorperazine,
116 patients
effects of each
greater than
placebo; consider-
ably more
CNS side effects
with THC than
prochlorperazine
Nausea and
Oral placebo or
93% patients had
Chang et al.,
emesis due to
10 mg/m
2
a reduction in
1979
cancer
THC every 3
nausea and
chemotherapy; 15
hours for a
vomiting, 53%
patients
total of 5
had an excellent
doses, THC
response, 40%
(17 mg) laced
had a fair
cigarettes of
response; plasma
placebo were
THC levels
given if vomiting
7.1 ± 6.9
occurred
(mean ± SD)
ng/ml. Side
effects
included sedation,
tachycardia, few
other side effects
Pain due to
Oral placebo and
Pain relief,
Noyes, et al,
advanced cancer;
5, 10, 15 or
elevated mood,
1975
10 patients
20 mg THC
appetite
stimulation,
drowsiness,
slurred
speech, mental
clouding
Pain due to
Placebo, 10 and
THC produced a
Noyes et al.
advanced cancer;
20 mg THC, and
similar degree
1975
34 patients
60 and 120
of analgesia,
codeine
with greater
potency than
codeine.
THC CNS side
effects
included sedation,
mental clouding,
ataxia,
and disorientation
Spasticity related
Oral 10 or 15 mg
Improvement in
Brenneisen et
to multiple
THC, rectal dose
passive mobility
al., 1996
schlerosis; 2
of 5 or 10
and walking
patients
mg THC
ability
Spasticity related
Oral 2.5 to 15
Significant
Ungerleider et
to multiple
mg THC once or
subjective
al., 1987
schlerosis; 13
twice daily or
improvement in
patients
placebo
spasticity at 7.5
mg THC and
higher,
no significant
improvement
in objective
measurements
Spasticity related
Oral 5 to 15 mg
5 of 8 patients
Clifford, 1983
to multiple
THC
had mild
schlerosis; 8
subjective
patients, single
improvement in
blind
tremor. 2 of 8
patients had both
objective and
subjective
improvement
Spasticity related
Placebo, or
Decrease in
Petro and
to multiple
5 or 10 mg
spasticity
Ellenberger,
schlerosis; 9
THC
compared
1981
patients
to placebo
treatment,
minimal side
effects
Spasticity and
Oral placebo,
THC and codeine
Maurer et al.,
pain due to
THC (5 mg), or
had analgesic
1990
spinal cord injury;
codeine (50 mg)
effect compared
1 patient
to the placebo
treatment. THC
had a beneficial
effect
on spasticity
whereas codeine
did not
Glaucoma, 6
Oral placebo
Pain relief
Merritt et
patients
or 5, 10, 15
elevated mood,
al, 1980
and 20 mg THC
appetite
stimulation,
drowsiness,
slurred speech,
mental clouding
Ten subjects
Intravenous THC
Decreased intra
Cooler and
with normal
(0.022 or 0.044
ocular pressure
Gregg, 1977
intra ocular
mg/kg)
by a mean of 37%
pressure
Nausea and
Oral 10 mg/m
2
In 20 courses of
Sallan et al.,
emesis due to
THC or placebo
THC, 5 resulted
1975
cancer
in no vomiting,
chemotherapy;
9 resulted in a
refractory to
reduction of
other antiemetics
vomiting, 3
resulted in no
decrease in
vomiting,
and 2 were
unevaluable. THC
was significantly
better than
placebo
in decreasing
vomiting.
When marijuana is used illegally as a recreational psychoactive drug, the active ingredient &Dgr;
9
THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized &Dgr;
9
THC in the inhaled smoke is absorbed within seconds and delivered to the brain efficiently. Table 2 and references 19-20 describe the pharmacokinetics of the administration of &Dgr;
9
THC. As can be seen, inhalation is the preferred route of delivery for &Dgr;
9
THC. When compared to oral delivery, inhalation provides a more rapid onset of pharmacological action and peak plasma levels. The effects achieved via inhalation are comparable to those achieved when the drug is administered intravenously, but inhalation is a much less invasive technique.
TABLE 2
Pharmacokinetics of &Dgr;
9
THC Given Orally, Intravenously or by Smoking
Onset of
% Dose in
Pharmacological
Peak Plasma
Route
Dose
Plasma
Action
Levels
References
Oral, sesame
2.5, 5, or
10 to 20%
0.5 to 1 hour
120-480 min
(PDR, 1995)
oil in gelatin
10 mg
capsules
Oral, in
20 mg
4 to 12%
120-180 min
60-90 min
(Ohlsson, et
cookies
al., 1980)
Intravenous,
5 mg
100%
10 min
3 min
(Ohlsson, et
bolus
al., 1980)
Smoking
13 mg
8 to 24%
10 min
3 min
(Ohlsson, et
(THC lost to
al., 1980)
side stream
smoke and
pyrolysis
Currently, the sources of &Dgr;
9
THC for patients who could benefit from the drug are very limited. An oral form of &Dgr;
9
THC (MARINOL) is marketed as a treatment for nausea and vomiting related to cancer chemotherapy, and as an appetite stimulant in patients suffering from AIDS wasting syndrome. In MARINOL, pharmaceutical grade &Dgr;
9
THC is dissolved in sesame oil, encapsulated in gelatin capsules and delivered orally. However, when the drug is taken orally, the absorption is slower and more variable than when inhaled, with an onset of action between 30 minutes and 2 hours (Table 2). Alternatively, some cancer patients do manage to obtain and smoke marijuana in order to alleviate such conditions as nausea and vomiting due to chemotherapy. This is, however, technically illegal and is thus obviously a less than ideal treatm
Byron Peter R.
Lichtman Aron H.
Martin Billy R.
Peart Joanne
Jones Dameron L.
Rafa Michael J.
Virginia Commonwealth University
Wells Lauren Q.
Whitham Curtis & Christofferson, P.C.
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